Abstract

2361

The effects of serotonin (5-HT) on tumor growth are inconsistent. We investigated whether a decreased level of 5-HT affected tumor growth using 5-HT transporter knockout (5-HTT-/-) mice, which showed 5-HT depletion. When cancer cells were injected subcutaneously into both wild-type-mice and 5-HTT-/- mice, the tumor growth was markedly attenuated in 5-HTT-/- mice. However, when we applied 5-HTT inhibitors to the wild type mice bearing tumors, they did not inhibit tumor growth. 5-HT levels in the blood, forebrain, tumors of 5-HTT-/- mice bearing tumors were significantly smaller than those of their 5-HTT+/+ littermates. The endothelial nitric oxide synthase (eNOS) expressions in tumors were reduced in 5-HTT-/- mice compared with 5-HTT+/+ mice. The stimulations with 5-HT (1-50 μM) induced eNOS expressions in human umbilical vascular endothelial cells (HUVEC) in a concentration-dependent manner. When we measured activations of multiple signaling pathways by using a high-throughput phospho-specific antibodies platform, 5-HT stimulated the ERK1/2 in HUVEC. Moreover, we found that physiological level of 5-HT induced phosphorylation of both ERK1/2 and eNOS in HUVEC. HUVEC expressed both 5-HT2B and 5-HT2c receptors. SB204741, a specific 5-HT2B receptor inhibitor, blocked 5-HT-induced ERK1/2 and eNOS phosphorylations, while RS102221, a specific 5-HT2C receptor inhibitor, did not in HUVEC. SB204741 reduced tumor growth in vivo but RS102221 did not. SB204741 reduced microvessel densities in tumor and inhibited the proliferation of HUVEC in vitro. These results suggest that regulation of 5-HT and 5-HT receptors, especially 5-HT2B receptor, may serve as a therapeutic strategy in cancer therapy.